Human ether-a-go-go related gene (hERG) K+ channels: Function and dysfunction
Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, NSW 2010, Australia. Progress in Biophysics and Molecular Biology
(Impact Factor: 2.27).
12/2008; 98(2-3):137-48. DOI: 10.1016/j.pbiomolbio.2008.10.006
The human Ether-a-go-go Related Gene (hERG) potassium channel plays a central role in regulating cardiac excitability and maintenance of normal cardiac rhythm. Mutations in hERG cause a third of all cases of congenital long QT syndrome, a disorder of cardiac repolarisation characterised by prolongation of the QT interval on the surface electrocardiogram, abnormal T waves, and a risk of sudden cardiac death due to ventricular arrhythmias. Additionally, the hERG channel protein is the molecular target for almost all drugs that cause the acquired form of long QT syndrome. Advances in understanding the structural basis of hERG gating, its traffic to the cell surface, and the molecular architecture involved in drug-block of hERG, are providing the foundation for rational treatment and prevention of hERG associated long QT syndrome. This review summarises the current knowledge of hERG function and dysfunction, and the areas of ongoing research.
Available from: jpet.aspetjournals.org
- "However, the seizure phenotype is obviously more common in LQT2 (36/77, 47%) than average and all other subtypes of LQT syndrome. Inhibition of the hERG channel by drugs causes acquired LQT2 (Roden, 2004; Perrin et al., 2008; Berger et al., 2010; Zhou et al., 2011). "
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ABSTRACT: hERG and KCNQ channels are two classes of voltage-gated potassium (Kv) channels. Specific mutations have been identified that are causal for type II Long QT (LQT2) syndrome and neonatal epilepsy, Benign Familial Neonatal Convulsions (BFNC). Increasing evidence from clinical studies suggests that LQT2 and epilepsy coexist in some patients. Therefore, an integral approach to investigate and treat the two diseases is likely more effective. In the current study, we found NS1643 (1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea), a previously reported hERG activator, is also an activator of KCNQ channels. It potentiates the neuronal KCNQ2, KCNQ4 and KCNQ2/Q3 channels but not the cardiac KCNQ1. The effects of NS1643 on KCNQ2 channel include left shifting of V1/2 and slowing of deactivation. Analysis of dose-response curve of NS1643 revealed an EC50 value of 2.44 ± 0.25 μM. A hydrophobic phenylalanine (F137) that locates at the middle of region of the voltage-sensing domain (VSD) was identified critical for that NS1643 activity on KCNQ2. When testing NS1643 effects in rescuing LQT2 hERG mutants and the KCNQ2 BFNC mutants, we found it is particularly efficacious in some cases. Considering the substantial relationship between LQT2 and epilepsy, these findings reveal that NS1643 is a useful tool compound to elucidate the causal connection of LQT2 and epilepsy. More generally, this may provide a strategy in the development of therapeutics for LQT2 and epilepsy.
Available from: Amalendu P Ranjan
- "The corrected current with heart rate is defined as QTc
. This IKr or the hERG current is critical for ventricular repolarization and inhibition of IKr can induce QT prolongation which may result in life threatening ventricular arrhythmias
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ABSTRACT: Cardiac toxicity is the foremost reason for drug discontinuation from development to clinical evaluation and post market surveillance [Fung 35:293-317, 2001; Piccini 158:317-326 2009]. The Food and Drug Administration (FDA) has rejected many potential pharmaceutical agents due to QT prolongation effects. Since drug development and FDA approval takes an enormous amount of time, money and effort with high failure rates, there is an increased focus on rescuing drugs that cause QT prolongation. If these otherwise safe and potent drugs were formulated in a unique way so as to mitigate the QT prolongation associated with them, these potent drugs may get FDA approval for clinical use. Rescuing these compounds not only benefit the patients who need them but also require much less time and money thus leading to faster clinical translation. In this study, we chose curcumin as our drug of choice since it has been shown to posses anti-tumor properties against various cancers with limited toxicity. The major limitations with this pharmacologically active drug are (a) its ability to prolong QT by inhibiting the hERG channel and (b) its low bioavailability. In our previous studies, we found that lipids have protective actions against hERG channel inhibition and therefore QT prolongation.
Results of the manual patch clamp assay of HEK 293 cells clearly illustrated that our hybrid nanocurcumin formulation prevented the curcumin induced inhibition of hERG K+ channel at concentrations higher than the therapeutic concentrations of curcumin. Comparing the percent inhibition, the hybrid nanocurcumin limited inhibition to 24.8% at a high curcumin equivalent concentration of 18 muM. Liposomal curcumin could only decrease this inhibition upto 30% only at lower curcumin concentration of 6 muM but not at 18 muM concentration.
Here we show a curcumin encapsulated lipopolymeric hybrid nanoparticle formulation which could protect against QT prolongation and also render increased bioavailability and stability thereby overcoming the limitations associated with curcumin.
Available from: Amiram Goldblum
- "This cardiac potassium channel is voltage-activated. It has a relatively large inner cavity that allows drug molecules to enter and bind tightly to the channel pore   . Aromatic amino acid residues arranged in two rings of four amino acids each within the central cavity enhance interactions with aromatic groups of drugs and thus may lead to channel blockage, prevent potassium conduction, and eventually cause the drug-acquired LQTS [17e21]. "
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ABSTRACT: The human Ether-a-go-go-Related-Gene (hERG) potassium (K(+)) channel is liable to drug-inducing blockage that prolongs the QT interval of the cardiac action potential, triggers arrhythmia and possibly causes sudden cardiac death. Early prediction of drug liability to hERG K(+) channel is therefore highly important and preferably obligatory at earlier stages of any drug discovery process. In vitro assessment of drug binding affinity to hERG K(+) channel involves substantial expenses, time, and labor; and therefore computational models for predicting liabilities of drug candidates for hERG toxicity is of much importance. In the present study, we apply the Iterative Stochastic Elimination (ISE) algorithm to construct a large number of rule-based models (filters) and exploit their combination for developing the concept of hERG Toxicity Index (ETI). ETI estimates the molecular risk to be a blocker of hERG potassium channel. The area under the curve (AUC) of the attained model is 0.94. The averaged ETI of hERG binders, drugs from CMC, clinical-MDDR, endogenous molecules, ACD and ZINC, were found to be 9.17, 2.53, 3.3, -1.98, -2.49 and -3.86 respectively. Applying the proposed hERG Toxicity Index Model on external test set composed of more than 1300 hERG blockers picked from chEMBL shows excellent performance (Matthews Correlation Coefficient of 0.89). The proposed strategy could be implemented for the evaluation of chemicals in the hit/lead optimization stages of the drug discovery process, improve the selection of drug candidates as well as the development of safe pharmaceutical products.
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